Treatment of Co-Occurring Alcohol Use Disorders and Depression/Anxiety Disorders highlight the need, recognized by the NIAAA, to identify new targets/drugs for the treatment of alcoholism and its co- morbidities. Naltrexone a non-selective opioid receptor antagonist is one of the few therapeutics currently used in the treatment of alcoholism, validating the opioid receptor system as a relevant target for alcohol abuse. However, naltrexone shows highly variable eficacy in treatment seeking alcoholics and is plagued by side effects and consequent lack of compliance of use. We propose that the non-selective nature of naltrexone may be contributing to the variable efficacy and/or the side effects that limit compliance. Here, we propose to examine specifically the role of the delta opioid receptor (DOR) subtypes, DOR1 and DOR2 in alcohol related behaviors. We are particularly intrigued by the DOR as a target because it is involved in both alcohol consumption and anxiety, which is often co-morbid with alcohol abuse and is a key risk factor for relapse. In our preliminary studies we have found that drugs that target the DOR1 and DOR2 subtypes of opioid receptor have opposing effects on ethanol consumption. In addition, we have found that an antagonist at DOR2 and an agonist at DOR1 can act synergistically to reduce ethanol consumption clearly indicating that these two receptor subtypes are distinct targets with opposing actions. We also have preliminary evidence that the DOR1 may be a heterodimer of the DOR and the mu opioid receptor (MOR). In this proposal, we will examine which commercially available DOR ligands are effective for the reduction of ethanol consumption and ethanol withdrawal induced anxiety. We will also examine whether prolonged ethanol exposure alters the potency and/or efficacy of the DOR ligands, in particular the subtype selective ligands. As a third goal, we will determine whether the effects of any of the DOR drugs require expression of the other opioid receptors, in particular the MOR which could indicate that they target a DOR/MOR heterodimer to exert their effects. Together, these studies may validate the DOR as a target for alcohol abuse disorders, indentify the pharmacological profile of the most ideal ligands for alcohol abuse disorders, and perhaps provide in vivo relevance for the MOR/DOR heterodimer as a target. PUBLIC HEALTH RELEVANCE: These studies are designed to evaluate the role of DOR receptor subtype pharmacology on ethanol responses in the hopes of validating new opioid receptor targets for the treatment of alcohol related disorders with reduced side effect profiles. Specifically, we will examine the role of the DOR1 and DOR2 in alcohol consumption and co-morbid anxiety. We will also determine whether any DOR subtype selective drugs require expression of another opioid receptor.